SHANGHAI – When Beyondspring Pharmaceuticals Inc., a clinical-stage immuno-oncology biopharma started its U.S.-China development strategy for lead candidate plinabulin, getting a first-in-class drug past China's regulators was an unwieldy prospect, often taking years longer than the U.S. But after China's most recent round of regulatory reforms, things are looking up considerably. (See BioWorld Today, March 18, 2015.)

On Oct. 8, two powerful central government bodies – the General Office of the CPC Central Committee and the General Office of China's State Council – made a joint statement backing up many of the reforms proposed by the CFDA in May. (See BioWorld Today, May 15, 2017.)

The statement, referred to as the Opinion on Reform of the Review and Approval System for Drugs and Medical Devices, sets out several positive regulatory changes for innovative drug developers, leveling the playing field for both Chinese and foreign biopharmas. For example, one of the major changes is the CFDA's newfound willingness to accept foreign data alongside Chinese patient data in submissions for the first time.

Nimble startups such as Beyondspring, which counts Dalian City in Qingdao and New York in the U.S. as its headquarters, are moving quickly to reap the rewards.

But in the case of Beyondspring, the two rule reforms that most excite the firm's CEO and co-founder, Lan Huang, are slightly different; one is the establishment of conditional approvals and the other is the introduction of a patent linkage system. With clinical trials already well underway, those reforms stand to lengthen the time Beyondspring can bring plinabulin to patients, should the CFDA grant approval.

Conditional approval, a new option

China's willingness to grant conditional approvals – following the U.S.'s example – could knock as much as two years off the clinical development timelines for plinabulin, an I.V.-administered agent being studied in phase III global trials for the treatment of non-small-cell lung cancer (NSCLC) and in a phase II/III program for the prevention of chemotherapy-induced neutropenia.

"We are encouraged by recent guidelines from the China FDA aimed at accelerating the approval process for new drugs in China, which leads us to believe that favorable efficacy trends observed in interim phase III results could fast-track plinabulin for NDA submissions in China as early as 2018, and position plinabulin for conditional approval in China for both of its lead indications as early as 2019," Huang said in a quarterly report.

China's conditional approvals may be granted to drugs and devices that offer new solutions for treating life-threatening diseases or address critical unmet medical needs, as long as early and midstage study data indicate their efficacy and predict their clinical value, as explained in a legal note from Ropes & Gray LLP.

"Without this conditional approval," Huang told BioWorld Asia, "we would have to wait until all the data read out to statistical significance. For neutropenia, it will be delayed one year and for lung cancer it will be delayed for two years. For lung cancer, we are using overall survival as a primary endpoint, so you have to wait until everybody dies to achieve statistical significance."

Similar to the U.S., the sponsor must continue to conduct the phase III study while the drug is on the market and get formal market authorization after the data provide full results. "The drug can be on the market selling a year or two years ahead of the full approval. That is significant," said Huang.

What is happening in China could also have positive ramifications for Beyondspring's U.S. trials. Another aspect of the reforms is to open up hospitals sites for clinical trials that may speed up patient enrollment in China. (Huang, however, admitted it is unclear how many new clinical trial sites will be up to speed in the near term to run clinical trials for new drugs.) If those go as planned, Huang is hopeful that "our enrollment speed is going to go up and that patient data will ultimately support the global filing; so the global filing could potentially also be sped up."

Beyondspring enrolled the first patient in China for the neutropenia trial at the end of October.

The company would like to see plinabulin become the new standard of care for neutropenia, a common chemotherapy side effect that destroys white blood cells, opening up cancer patients to severe infections and sepsis with a high risk of mortality.

Plinabulin is given as an I.V. infusion 30 minutes after chemotherapy, unlike the current standard of care, G-CSF, which is given 24 hours after chemo. In addition, plinabulin is not associated with bone pain, a frequent G-CSF side effect.

Patent linkage and extension

Although China is not well-known for its patent protections, it is improving considerably. Huang pointed to the establishment of the patent linkage and extension as a crucial feature of the new policy.

"The patent linkage and patent extension for innovative drugs after NDA is very important because innovative drugs take a long time to get to the market," she said. "You really want patent protection so you can sustain peak sales for a little bit longer and so the company can recoup investment to do more innovation – this is another great policy for innovative drug companies." Under the new patent linkage rules, generic manufacturers are required to notify patent holders of their applications with the CFDA in order to allow time for patent holders to file patent litigation claims.

Katherine Wang, a lawyer with Ropes & Gray, pointed out there are still several elements to be worked out, however. The CFDA/CDE review of the generic application will not automatically be stayed during patent disputes. Further, China's Orange Book – the listing of all approved drugs – has not formally come out yet, but that is expected to come shortly. Specific rules regarding how the patent protection will be rolled out are also lacking.

If China follows the patent linkage and extension system already in place in the U.S., EU and Japan, that could lead to a five-year patent extension after NDA approval.

The extension is based on the amount of time for clinical trial and review, calculated as half of the clinical trial time plus the full review time. If that adds up to more than five years, then the full five-year patent extension is possible. Since plinabulin entered the clinic in 2006 and is expected to complete its phase III trial in 2018, it would be able to apply for a full patent extension.

Huang said the government is serious about protecting innovators and enforcing patents and pointed to the recent case of Viagra (sildenafil) in China. Before China granted the Viagra patent, many factories were making it, but shortly after the patent was granted, the government effectively closed the factories.

But the new patent policy does not shut out the generics makers completely.

"But there is a twist: The day a drug loses its patent, the CFDA will approve the generics," said Huang. "But in a way, it is good for everybody. You have the government as a judge; it is not being regulated by the street but by the CFDA."